L-carnitine delays the killing of cultured hepatocytes by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
The role of fatty acid metabolism in chemical-dependent cell injury is poorly understood. Addition of L-carnitine to the incubation medium of cultured hepatocytes delayed cell killing initiated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Protection by L-carnitine was stereospecific and observed as late as 1 h following addition of MPTP. D-Carnitine, but not iodoacetate, reversed the L-carnitine effect. Monoamine oxidase A and B activities, MPTP/N-methyl-4-phenyl-pyridinium levels, and MPTP-dependent loss of mitochondrial membrane potential measured by release of [3H]triphenylmethylphosphonium were not altered by addition of L-carnitine. Significant changes in MPTP-induced depletion of total cellular ATP did not occur with excess L-carnitine. Although the mechanism of cytoprotection exerted by L-carnitine remains unresolved, the data suggest that L-carnitine does not significantly alter: (i) mitochondrial-dependent bioactivation of MPTP; (ii) MPTP-dependent loss of mitochondrial membrane potential; or (iii) MPTP-mediated depletion of total cellular ATP content. We conclude that alterations of fatty acid metabolism may contribute to the toxic consequences of exposure to MPTP. Moreover, the lack of L-carnitine-mediated cytoprotection of monolayers incubated with 4-phenylpyridine or potassium cyanide suggests: (i) a link between fatty acid metabolism and mitochondrial membrane-mediated, bioactivation-dependent cell killing; and (ii) that inhibition of NADH dehydrogenase may not totally explain the mechanism of MPTP cytotoxicity.
Snyder
J W
JW
Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Kyle
M E
ME
Ferraro
T N
TN
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000032:analysis / Q000494:pharmacology*; D015655:1-Methyl-4-phenylpyridinium / Q000032:analysis; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D007700:Kinetics; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000378:metabolism / Q000502:physiology; D008995:Monoamine Oxidase / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D010656:Phenylephrine; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D011190:Potassium Cyanide; D015655:1-Methyl-4-phenylpyridinium; D002331:Carnitine